Discontinuing CTX not recommended in malaria regions

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KemriCotrimoxazole (CTX) discontinuation is inferior to CTX continuation among ART-treated, immune-reconstituted HIV-infected adults living in a malaria-endemic region, according to a trial by Christina Polyak at the Walter Reed Army Institute of Research and University of Washington, and colleagues.

These trial findings were important for December 2014 World Health Organisation guidelines recommending that CTX prophylaxis be continued regardless of CD4 cell count or HIV/Aids clinical stage in settings where malaria is endemic and/or severe bacterial infections are common.

The trial enrolled 500 HIV-infected adults living in a malaria-endemic region of Kenya who had been treated with ART for approximately 18 months, who had a CD4 count of >350 cells/mm3, and who were taking CTX. After 12 months of follow-up, the combined rate of morbidity events (malaria, pneumonia, and diarrhoea) and non-trauma mortality events was significantly higher in the CTX discontinuation arm than in the CTX continuation arm (IRR = 2.27, 95% CI 1.52-3.38; p < 0.001). The difference in this primary outcome between the trial arms was driven by malaria morbidity — there were 33 cases of malaria in the CTX discontinuation arm but only one case in the CTX continuation arm. Study limitations included lack of blinding and statistical constraints from lower than expected incidence of morbidity. However, analyses were strengthened by 98% retention rates in both arms.

The authors state, “Malaria endemicity may be the most relevant factor to consider in the decision to stop CTX after ART-induced immune reconstitution in regions with high infectious disease prevalence.”

Abstract
Background
Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organization (WHO) for HIV-1-infected individuals in settings with high infectious disease prevalence. The WHO 2006 guidelines were developed prior to the scale-up of antiretroviral therapy (ART). The threshold for CTX discontinuation following ART is undefined in resource-limited settings.
Methods and Findings
Between 1 February 2012 and 30 September 2013, we conducted an unblinded non-inferiority randomized controlled trial of CTX prophylaxis cessation versus continuation among HIV-1-infected adults on ART for ≥18 mo with CD4 count > 350 cells/mm3 in a malaria-endemic region in Kenya. Participants were randomized and followed up at 3-mo intervals for 12 mo. The primary endpoint was a composite of morbidity (malaria, pneumonia, and diarrhea) and mortality. Incidence rate ratios (IRRs) were estimated using Poisson regression.
Among 538 ART-treated adults screened, 500 were enrolled and randomized, 250 per arm. Median age was 40 y, 361 (72%) were women, and 442 (88%) reported insecticide-treated bednet use. Combined morbidity/mortality was significantly higher in the CTX discontinuation arm (IRR = 2.27, 95% CI 1.52–3.38; p < 0.001), driven by malaria morbidity. There were 34 cases of malaria, with 33 in the CTX discontinuation arm (IRR = 33.02, 95% CI 4.52–241.02; p = 0.001). Diarrhea and pneumonia rates did not differ significantly between arms (IRR = 1.36, 95% CI 0.82–2.27, and IRR = 1.43, 95% CI 0.54–3.75, respectively). Study limitations include a lack of placebo and a lower incidence of morbidity events than expected.
Conclusions
CTX discontinuation among ART-treated, immune-reconstituted adults in a malaria-endemic region resulted in increased incidence of malaria but not pneumonia or diarrhea. Malaria endemicity may be the most relevant factor to consider in the decision to stop CTX after ART-induced immune reconstitution in regions with high infectious disease prevalence. These data support the 2014 WHO CTX guidelines.

PLOS material
PLOS Medicine abstract


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